N-(2-arylethyl)benzylamines as antagonists of the 5-HT6 receptor

Abstract

The present invention provides compounds of formula (I), which are antagonists of the 5-HT 6 receptor.

1. A method of treating Alzheimer's disease comprising administering to a patient in need thereof an effective amount of a combination of a 5-HT 6  receptor antagonist and a cholinesterase inhibitor, or pharmaceutically acceptable salts thereof, wherin the 5-HT 6  receptor antagonist is of structural formula I: 
       
         
           
           
               
               
           
         
       
       wherein X is selected from the group consisting of —O—, —NH—, —S—, —SO 2 —, —CH 2 —, —CH(F)—, —CH (OH)—, and —C(O)—;
 R 1  is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused; 
 R 2  is selected from the group consisting of hydrogen and C 1 -C 3  alkyl; 
 R 3  is selected from the group consisting of hydrogen, fluoro, and methyl; and 
 R 4  is selected from the group consisting of hydrogen, allyl, C 2 -C 4  alkyl, fluorinated C 2 -C 4  alkyl, optionally substituted phenyl, optionally substituted phenylsulfonyl, optionally substituted benzyl, and optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, provided that R 4  is not optionally substituted phenylsulfonyl when X is —SO 2 —, —CH 2 —, —CH(F)—, —CH(OH)—, or —C(O)—. 
 
     
     
       2. The method of  claim 1 , wherein X is —O—; or a pharmaceutically acceptable salt thereof. 
     
     
       3. The method of  claim 2 , wherein R 3  is hydrogen; or a pharmaceutically acceptable salt thereof. 
     
     
       4. The method of  claim 3 , wherein R 4  is selected from the group consisting of C 2 -C 4  fluorinated alkyl and optionally substituted phenyl; or a pharmaceutically acceptable salt thereof. 
     
     
       5. The method of  claim 4 , wherein R 1  is optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is benzofused; or a pharmaceutically acceptable salt thereof. 
     
     
       6. The method of  claim 5 , wherein R 4  is fluorinated C 2 -C 4  alkyl; or a pharmaceutically acceptable salt thereof. 
     
     
       7. The method of  claim 6 , wherein the 5-HT 6  receptor antagonist is N-(2-(6-fluoro-1H -indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylamine, or a pharmaceutically acceptable salt thereof. 
     
     
       8. The method of  claim 6 , wherein the 5-HT 6  receptor antagonist is N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride. 
     
     
       9. The method of  claim 8 , wherein the cholinesterase inhibitor is tacrine. 
     
     
       10. The method of  claim 8 , wherein the cholinesterase inhibitor is donepezil.